For the past 30 years, the dopamine hypothesis has been the leading neurochemical model of schizophrenia. The dopamine hypothesis is based upon observations that amphetamine-like dopamine releasing agents induce a psychotomimetic state that closely resembles schizophrenia and that agents that block dopamine receptors (e.g., chlorpromazine, haloperidol) are clinically beneficial in the treatment of schizophrenia. The dopamine hypothesis posits that symptoms of schizophrenia reflect functional hyperactivity of brain dopaminergic symptoms, primarily in the mesolimbic and mesocortical brain regions. Despite its heuristic value, however, there are several limitations of the dopamine hypothesis that have contributed to limitations in clinical treatment in schizophrenia. First, amphetamine psychosis provides an accurate model only for the positive symptoms of schizophrenia (e.g., hyperactivity, hallucinations). In contrast, amphetamine administration does not lead to the development of negative symptoms (e.g., blunted affect, emotional withdrawal) or cognitive dysfunction similar to that observed in schizophrenia. A significant percentage (20-50%) of schizophrenic patients continue to show prominent negative symptoms and thought disorder despite optimal treatment with dopamine-blocking agents, indicating that new treatment approaches are necessary. Second, for the majority of schizophrenic patients no clear disturbances of dopaminergic neurotransmission have been demonstrated. Thus, to the extent that functional dopaminergic hyperactivity does exist, it may be secondary to a more fundamental disturbance in other neurotransmitter systems. Antidopaminergic treatment, therefore, while controlling symptoms may not address underlying pathophysiology.
A potential direction for the development of a new treatment approach first became available in the late 1950's with the development of phencyclidine (PCP, "angel dust"). PCP was initially developed for use as a general anesthetic. In early clinical trials, PCP and related agents (e.g., ketamine) were found to induce psychotic symptoms that closely resembled those of schizophrenia. As opposed to amphetamine psychosis, PCP psychosis incorporated both negative and positive symptoms of schizophrenia. Moreover, PCP uniquely reproduced the type of cognitive dysfunction seen in schizophrenia. Mechanisms underlying PCP-induced psychosis remained largely unknown until the initial description of brain PCP receptors in 1979. Subsequent research in the early 1980s demonstrated that the PCP receptor constitutes a binding site located within the ion channel associated with N-methyl-D-aspartate (NMDA)-type glutamate receptors, and that PCP and related agents induce their psychotogenic effects by blocking NMDA receptor-mediated neurotransmission. This finding led to the suggestion (Reference 15; Reference 5) that endogenous dysfunction or dysregulation of NMDA receptor-mediated neurotransmission might contribute significantly to the etiology of schizophrenia, and, in particular, might lead to the expression of neuroleptic-resistant negative and cognitive symptoms. Further, it raised the possibility that medications that could potentiate NMDA receptor-mediated neurotransmission might be beneficial in the treatment of neuroleptic-resistant signs and symptoms of schizophrenia.
Prior to discovery of the glycine binding site in 1987, it was found that administration of oral glycine to rodents at high doses similar to those used later by the present inventor leads to reversal of behavioral effects induced by PCP Reference 14), indicating that that behavioral essay may be sensitive to the anti-psychotic effects of NMDA augmenting agents.
NMDA receptors are primarily activated by glutamate, which serves as the major excitatory neurotransmitter in cortex. Exogenous glutamate cannot be administered effectively, however, because (1) glutamate does not cross the blood-brain barrier, (2) glutamate activates several types of receptors other than NMDA receptors, and (3) activation by glutamate analogs that cross the blood-brain barrier may lead to overexcitation of cortical neurons, resulting in neuronal degeneration (excitotoxicity). A potential alternate approach for potentiating NMDA receptor-mediated neurotransmission became available in 1987 with the demonstration that glycine acts as an allosteric modulator at the NMDA receptor complex (Reference 7). This finding raised the possibility that exogenously administered glycine might selectively potentiate NMDA receptor-mediated potentiation and might, therefore, lead to clinical improvement in schizophrenic patients with prominent neuroleptic-resistant symptomatology. Limitations to the use of glycine were (1) it was unknown to what extent exogenously administered glycine might permeate the CNS, (2) it was unknown to what extent glycine regulation of NMDA receptor-mediated neurotransmission would be of physiological relevance in vivo, and (3) it was unknown to what extent augmentation of NMDA receptor-mediated neurotransmission might, in fact, lead to clinical improvement.
Subsequent to the discovery of the glycine binding site in 1987, several small clinical trials were attempted which were suggestive of possible beneficial clinical effects but which failed to demonstrate efficacy using standard statistical approaches. Waziri in 1988 (Reference 12) published regarding the treating of 11 schizophrenic patients with doses of 5-25 g/day in an open study which lasted 9 months. They reported improvement in 4 of the 11 patients, but failed to provide a control group or statistical analysis of their results. Costa et al., in 1990 (Reference 2) published their work on treating 6 patients with doses of 15 g/day of glycine in a 5 week open design, and observed positive responses in 2 patients, as reflected in a greater than 30% decrease in symptoms as measured by the Brief Psychiatric Rating Scale (BPRS). However, overall statistical analysis was not performed, and independent analysis of their published data does not reveal a statistically significant effect (t=1.89, p=0.12). A subsequent study (Reference 13) of 18 patients in a double-blind study of 15 g/day of glycine vs. placebo showed significant improvement in Clinical Global Impression (CGI), but did not show significant improvement in either the BPRS or a scale developed specifically for the assessment of negative symptoms, the Schedule for Negative Symptoms (SANS). Although it was concluded by these authors that use of higher doses of glycine might be required to demonstrate efficacy, no follow-up studies were conducted. Rosse et al., (Reference 11, 1989) administered 10.8 g/day glycine to 6 chronic schizophrenic subjects for periods of 4 days to 8 weeks in an open-design but failed to observe overall clinical efficacy. These authors also concluded that this treatment approach was limited by the poor CNS permeation of glycine. Until 1994, no clinical studies were performed by any group with doses greater than 25 g/day, and the practicality of using glycine at higher doses was not determined.
The first study to be performed with higher doses of glycine was initiated by the applicant in 8/89. In this study, 14 chronic schizophrenic subjects with neuroleptic-resistant symptomatology were treated with 0.4 g/Kg/day (approx. 30 g/day) in a double-blind placebo-controlled fashion and positive and negative symptoms were monitored using the Positive and Negative Symptom Scale (PANSS). This study validated the use of high doses of glycine in that the medication was well tolerated. Moreover, preliminary encouraging results were obtained such that significant improvement in negative symptoms was observed in the glycine-treated subjects, whereas no similar improvement was observed in those treated with placebo. However, the study remained inconclusive in that no significant difference was observed between the glycine- and placebo groups. Results of this study were published in August, 1994 (Javitt et al., 1994, Reference 6).